Heart failure (HF) is responsible for over a million hospital admissions annually in the US, and is the leading discharge diagnosis for patients over 65. Nearly half of the people admitted for HF have HF with preserved ejection fraction (HFpEF). HFpEF is associated with reduced quality of life and reduced survival, equal to that of patients with heart failure with reduced ejection fraction (HFrEF). Unfortunately, there are no known pharmacologic therapies that consistently improve either the morbidity or mortality associated with HFpEF. Several large trials of neurohormonal antagonists, agents known to improve survival in HFrEF, failed to establish benefit in HFpEF, suggesting that the mechanisms at play in HFpEF may be inadequately explained by those implicated in HFrEF. An early paradigm of HFpEF pathophysiology was that a stiff left ventricle leads to elevated filling pressures during exercise, resulting in shortness of breath. However, it is now recognized that HFpEF is a much more complex syndrome with important contributions from the periphery-including the skeletal muscle and the microvasculature. The broad working hypothesis of this proposal is that abnormalities in the skeletal muscle and the microvasculature play important roles in the exercise limitation seen in heart failure, in general, and in HFpEF specifically. This proposal seeks to demonstrate the relationships between exercise and (1) skeletal muscle mitochondrial oxidative capacity and (2) the diffusion capacity of oxygen to move from the capillary to the mitochondria. In Aim 1, skeletal muscle mitochondrial oxidative capacity will be determined non-invasively using MRI and near-infrared spectroscopy techniques, while Aim 2 will investigate diffusion capacity through maximal limb exercise with concurrent sampling of venous blood and measurements of arterial inflow. We hypothesize that patients with HFpEF will have greater impairments in mitochondrial function and diffusion capacity than patients with HFrEF or hypertensive controls. In Aim 3, we will randomize patients with HFpEF to inorganic nitrate, an agent known to improve exercise capacity and with the potential to affect both skeletal muscle mitochondrial oxidative capacity and diffusion capacity, to determine the relative contributions of these peripheral mechanisms to exercise capacity in HFpEF. Demonstration of an important role of these peripheral factors would open new avenues of investigation into ways to improve exercise capacity in HFpEF. Dr. Zamani is a heart failure and transplant cardiologist with experience in patient-oriented research in HFpEF. His long-term goal is to become a leader in the peripheral manifestations of heart failure and identify how abnormalities in the periphery impact exercise capacity. His patient-oriented career development training plan includes mentoring by experts in heart failure, exercise physiology, mitochondrial function, nitric oxide biology, and arterial hemodynamics. His proposed studies leverage the facilities and expertise available to him at the University of Pennsylvania, with important collaborations with outside faculty members.